Intravenous anaesthetic agents and anaesthetic consideration

Intravenous induction agents,propofol, thiopentone and benzodiazapine

1. INTRAVENOUS INDUCTION AGENTS MODERATOR- DR. SHUCHI NIGAM PRESENTER- DR. MITUL MUKHERJEE

2. CONTENT Classification Pharmacokinetics Pharmacodynamics Uses Dosage

3. CLASSIFICATION Classified according to their chemical structure and include : Barbiturates – Thiopental , methohexital Phenols – Propofol Benzodiazepines – Midazolam , diazepam, lorazepam Imidazoles - Etomidate Phencyclidines – Ketamine

4. What are the IV induction drug These are drugs that when given intravenously in appropriate dose, cause a rapid loss of consciousness.

5. Ideal IV induction agent - Physical properties : 1.Water soluble & stable in solution 2. Stable on exposure to light 3. Long shelf life 4. No pain on intravenous injection 5. Low incidence of thrombophlebitis 6 . Cheap

6. Pharmacokinetic Properties: Rapid onset within one arm-brain circulation time. Quick redistribution to vessel-rich tissues. Fast clearance and metabolism. No active metabolites.

7. Pharmacodynamic Properties: High therapeutic ratio. Minimal cardiovascular and respiratory effects. No histamine release or hypersensitivity reactions. No emetic effects. No involuntary movements. No emergence reactions. No hangover effect. No adrenocortical suppression.

8. PROPOFOL Chemically-  2,6-diisopropylphenol (an alkylphenol derivative) is an oily compound that is insoluble in water. Therefore, it requires a lipid vehicle for emulsification.

9. preparations  include: Contents:  1% propofol, 1.2% egg lecithin, 2.25% glycerol, 10% soybean oil. Antimicrobial agent:  Disodium edetate (0.05mg/ml) pH:  ~7 (6-8.5) All formulations commercially available are stable at room temperature, are not light sensitive, and may be diluted with 5% dextrose in water. (not less than 2mg/cc or 0.2% as there is danger of breakage of emulsion form)

10. Ampofol (Low Lipid Emulsion): Contents:  1% propofol, 0.6% egg lecithin, 5% soybean oil. Preservatives:  None, due to low lipid content. Note:  Equipotent to normal preparation, but causes more pain on injection and has less bacterial growth. Non-Lipid Formulation: Contents:  Cyclodextrin as solubilizing agent. More painful on intravenous administration.

11. Propofol derivative- Fospropofol - P ro-drug for propofol which is converted to propofol within a few minutes after i.v. injection. Induction of anaesthesia is delayed and recovery is correspondingly slow. About 1.86 mg of fospropofol sodium is the molar equivalent of 1 mg propofol.

12. Mechanism of action GABA A Receptor: Binding:  Propofol binds to the β subunit of the GABA A receptor, with the γ2 subunits also contributing to its modulatory effects. Mechanism:  It prevents the dissociation of GABA from the receptor. Effect:  This leads to prolonged activation of the receptor. Result:  Chloride influx occurs, causing hyperpolarization and inhibition of post-synaptic neurons.

13. Additional Actions: Inhibits acetylcholine (ACH) release in the hippocampus through GABA A action. Increases dopamine in the nucleus accumbens , contributing to a sense of well-being. Decreases serotonin in the area postrema, providing anti-emetic effects.

14. Pharmacokinetics Metabolism and Excretion:  Propofol is oxidized and conjugated in the liver, then excreted by the kidneys. There is also some extra-hepatic clearance, likely occurring in the kidneys and lungs. Enzyme Interaction:  It acts as a competitive inhibitor of CYP3A4, which increases the duration of action of midazolam. Distribution and Elimination:  After a single bolus dose, propofol levels decrease rapidly due to redistribution and elimination, with an initial distribution half-life of 2-8 minutes.

15. Context-Sensitive Half-Time:  The context-sensitive half-time is 10 minutes for infusions up to 3 hours and 40 minutes for infusions lasting 3-8 hours. EEG Activity:  Propofol starts to reduce EEG activity within 20 seconds, with peak effects occurring at 90 seconds.

16. Cardiac Output:  Decreased cardiac output, and therefore decreased hepatic blood flow, can impair its own clearance. Older patients experience a greater reduction in cardiac output. For example, an 80-year-old needs 50% of the dose required by a 20-year-old to achieve the same effect. Hepatic Disease:  Despite being cleared hepatically, no dose reduction is needed in hepatic disease due to efficient clearance and extra-hepatic clearance. Drug Interactions:  Propofol increases plasma levels of midazolam and remifentanil.

17. CONTEXT SENSITIVE HALF TIME

18. Pharmacodynamics Onset of hypnosis : After a dose of 2.5 mg/kg, hypnosis begins in about 20 seconds, with the peak effect occurring at 90 seconds. ED50 for loss of consciousness : Effective dose for 50% of the population (ED50) is between 1-1.5 mg/kg. Duration of action : This is dose-dependent. For a 2 mg/kg dose, the effect lasts between 5-8 minutes. Pediatric dosing : The highest dose is required for children under 2 years old.

19. Seizure activity : The agent can both suppress and cause seizures. Intracranial pressure (ICP) : It decreases ICP by 30-50% and also decreases cerebral perfusion pressure (CPP) and intraocular pressure by 30-40%. Cerebral autoregulation : Remains relatively intact.

20. Effects on respiration Induction dose : Has apnea incidence of 25-30% for 30 seconds or longer, especially when used with other medications Maintenance infusion : Decreases tidal volume by 40% and increases respiratory rate (RR) by 20%, at doses of 1 00 mcg/kg/min. Bronchodilatory properties : May have some ability to dilate the bronchi.

21. Effects on cardiovascular system Blood Pressure (BP) : Decreases by 25-40% due to reduced cardiac output (CO) and systemic vascular resistance (SVR). Hemodynamic Effect : Lags behind the hypnotic effect, taking about twice as long to manifest. Heart Rate (HR) : Can increase or decrease by about 10%. It inhibits the baroreceptor reflex tachycardia that usually results from hypotension.

22. Myocardial Blood Flow and Oxygen Consumption : Reduces both, but preserves the supply-to-demand ratio. Cardioprotective Effects : May have some at higher doses, especially when combined with inhaled anesthetics.

23. Uses Induction : Dose: 1-2.5 mg/kg based on total body weight. Adjustments: Based on age and reduced with premedication. Maintenance : Dose: 50-200 mcg/kg/min based on lean body weight. Adjustments: Tailored to the individual, with older and sicker patients requiring much less. Sedation : Dose: 25-75 mcg/kg/min. Anti-emetic : Dose: 10-20 mg IV intermittently or an infusion of 10 mcg/kg/min. Amnesia : Infusions greater than 30 mcg/kg/min usually cause amnesia.

24. Advantages Neuromuscular Blockade : Does not prolong neuromuscular blockade, but large doses can provide good intubating conditions without the need for paralysis. Malignant Hyperthermia (MH) : Not a trigger for MH. Adrenal Suppression : Does not cause adrenal suppression. Pleasant Dreams : Patients may experience pleasant dreams.

25. Adverse effects Anaphylactoid Reactions : Especially in individuals with multiple allergies. Pancreatitis : Likely due to hypertriglyceridemia, particularly in older patients, with longer duration and higher doses. Pain on Injection : Rarely, this can lead to thrombophlebitis of the vein.

26. Propofol Infusion Syndrome : Is rare, typically occurs with doses greater than 4mg/kg/hr for more than 48 hours. Symptoms include acute bradycardia leading to asystole, metabolic acidosis, rhabdomyolysis, hyperlipidemia , fatty liver, and hyperkalemia . Likely involves a genetic disorder related to fatty acid metabolism. In some cases, an increasing lipemia was the first indication of impending propofol infusion syndrome onset, so lipemia is a sign.

27. BARBITURATES Thiopental : Used for induction, cerebral protection, and as an anticonvulsant. Methohexital : Used for induction, especially in electroconvulsive therapy (ECT). Phenobarbital : Used for seizure suppression.

28. Classification by Duration of Action : Long-acting : Phenobarbitone Short-acting : Butobarbitone, Pentobarbitone Ultra short-acting : Thiopentone, Methohexitone Chemical Formation : Barbiturates are formed by the condensation of urea and malonic acid.

29. THIOPENTONE Physical Properties : Hygroscopic yellow powder with a garlic/onion taste, available in 500 mg or 1 g vials.

30. Clinical Use : Used as a 2.5% solution. Highly alkaline (pH 10.8) and bacteriostatic. Always prepared with normal saline (NS) or sterile water. Stable for 48 hours when freshly prepared. Refrigerated solution is stable for up to 2 weeks.

31. Dose- Induction of Anaesthesia- 3-4mg/kg Status epilepticus- single bolus dose of 3-5 mg /kg to treat an episode of convulsion f/b infusion ( 3-7mg/kg/hr) in status epilepticus refractory to conventional treatment. Cerebral protection- bolus of 3 mg/kg followed by an infusion of 5-6 mg/kg/hr to protect ischemic brain in neurosurgical patients.

32. Commercial Preparation : Contains its sodium salt with 6% anhydrous sodium carbonate ( Na₂CO ₃) to prevent precipitation of the acid form. Onset and Duration : Onset of action for IV injection: 10-20 seconds. Peak effect: 30-40 seconds. Duration of awakening: 5-15 minutes (dose: 3-5 mg/kg).

33. Induction Testing : Loss of eyelid and corneal reflexes used for testing induction. Reflexes : Cough and laryngeal reflexes are not depressed until high doses are given. Respiratory Effects : Bronchospasm and laryngospasm are likely in a light plane of anesthesia

34. Mechanism of Action GABA-A Receptor Binding : At low doses, the drug enhances the effect of GABA (gamma-aminobutyric acid). At high doses, it directly stimulates the GABA-A receptor, increasing chloride ion current and causing hyperpolarization of the neuron.

35. Pharmacokinetics Metabolism and Excretion : Most of the drug is metabolized in the liver and then excreted in the urine. Phenobarbital is an exception, with 60-90% excreted unchanged by the kidneys. Action Termination : The action of a single dose is terminated by rapid redistribution. Half-Time : The drug has a much longer context-sensitive half-time compared to propofol.

36. Pharmacodynamics Single dose duration : Lasts 5-10 minutes and redistributes to lean tissues. Wake-up time : Faster after methohexital compared to thiopental due to greater hepatic uptake. Recovery time : Barbiturates generally have a longer recovery time, which led to their replacement by propofol.

37. Cerebral Effects : Reduces cerebral metabolic rate of oxygen (CMRO₂), intracranial pressure (ICP), and cerebral blood flow (CBF). Preserves cerebral perfusion pressure (CPP) due to a greater reduction in ICP compared to mean arterial pressure (MAP).

38. Respiratory and CV Effects Dose-dependent depression : Can cause apnea after the induction dose. Peripheral vasodilation : Leads to negative inotropy (reduced force of heart muscle contraction). Increased heart rate : Rises by 10-36% due to the baroreceptor reflex, which can be harmful in patients with cardiac disease. QT interval : Can be prolonged, which is a concern for heart rhythm. In Hypovolemia : Can reduce cardiac output by up to 70%.

39. Adverse effects include: Garlic or onion flavors Allergic reactions Irritation of local tissues, and in rare cases, necrosis Induction of the P450 enzyme system Bronchoconstriction in individuals with asthma

40. Contraindications include: Porphyria Status asthmaticus Shock Myocardial infarction (MI)

41. Accidental intra-arterial injection can lead to several clinical features: Immediate intense pain Vasoconstriction, resulting in blanching of the extremity Cyanosis and potential gangrene The mechanism involves endothelial damage, which triggers an inflammatory response that may lead to arteritis and microembolization.

42. For treatment and prevention: Only use a 2.5% thiopentone solution. Keep the iv catheter in place. Inject saline through the iv catheter to dilute the drug. If the iv catheter is removed, administer a vasodilator in a more proximal location in the artery. Commonly used vasodilators include lidocaine, papaverine, and phenoxybenzamine. If thrombosis occurs, heparin or urokinase can be employed. Sympathetic blockade techniques, such as stellate ganglion or brachial plexus blockade, may be considered for relief.

43. BENZODIAZEPINES Benzodiazepines include: Midazolam (short-acting) Lorazepam and Temazepam (intermediate-acting) Diazepam (long-acting) Flumazenil (antidote, with a shorter half-life than most benzodiazepines)

44. The main pharmacological effects of benzodiazepines are: Anxiolysis Sedation Hypnosis Anticonvulsant action Spinal cord-mediated skeletal muscle relaxation Anterograde amnesia

45. Mechanism of Action Bind to GABA-A receptors, enhancing the response to GABA. Result in hypnotic, sedative, anxiolytic, amnestic, anticonvulsant, and muscle-relaxation effects. Increase seizure threshold. Maintain normal cerebral blood flow (CBF) to cerebral metabolic rate of oxygen (CMRO2) ratio.

46. Pharmacokinetics Midazolam: Onset : Rapid, less than 1 minute. Peak effect : 2-3 minutes. Distribution half-life : 6-15 minutes. Metabolism : Metabolized in the liver by CYP3A4 enzyme, producing the active metabolite 1-hydroxymidazolam. Accumulation : May occur in renal impairment, but not in those with normal renal function.

47. Lorazepam: Metabolism : Conjugated in the liver (not via CYP) to inactive metabolites. Renal impairment : Does not prolong effects, but liver failure can. Infusions : May lead to propylene glycol (solvent) toxicity. Remimazolam : Elimination : New ultrashort acting drug, eliminated by non-specific tissue esterases

48. Diazepam : Metabolism : metabolized by hepatic microsomal enzymes. Renal impairment : active metabolites may accumulate. Infusions : not recommended 0.1 mg/kg iv is effective in abolishing seizure activity.

49. Effects on respiratory system of benzodiazepines: Decreased muscular tone in the upper airway, increasing obstruction risk. Diminished response to elevated CO2. Weakened hypoxic response. Synergistic effects with opioids. Oral midazolam has minimal impact on respiration.

50. Cardiovascular Effects of benzodiazepines Small decrease in systemic vascular resistance (SVR) results in a slight reduction in blood pressure (BP). Baroreceptor reflexes are preserved. Cardiac output (CO) is maintained. In patients with elevated filling pressures, it functions like nitroglycerin, reducing filling pressures and increasing CO

51. Uses and Doses Premedication : anxiolysis, amnesia, and reduced PONV Midazolam: 7.5-15 mg PO or 0.5-2 mg IV Lorazepam: 2-4 mg PO or 0.25-1 mg IV ICU Sedation Midazolam: 1 to 2.5 mg iv (onset-30-60 sec,peak-3-5 min, duration-15-80 min) Avoid if possible due to risk of delirium and prolonged action Induction of Anesthesia Midazolam: 0.1 to 0.2mg/kg iv over 30-60 seconds, adjusted for age Diazepam: 0.5 to 1 mg/kg iv Reduction of PONV IV doses as low as 1 mg post-induction

52. Adverse effects include prolonged effects, post-operative delirium, and a deceptive sense of sleep without restorative benefits.

53. Flumazenil Competitive antagonist Short half-life may lead to rebound effects; infusion possible (30-60 mcg/min) Rapid onset (1-3 min) with a duration of 3-30 min May induce seizures in patients on chronic benzodiazepines

54. SUMMARY PROPOFOL MIDAZOLAM THIOPENTONE B.P DEC DEC DEC H.R NC/DEC INC INC S.V.R DEC DEC DEC C.O DEC NC DEC R.R T.V DEC DEC DEC CMRO2 DEC DEC DEC I.C.P DEC NC/INC DEC C.B.F DEC DEC DEC

55. PROPOFOL MIDAZOLAM THIOPENTONE Elimination half time (hrs) 0.5-1.5 1-4 ~10 hrs Vd (L/kg) 3.5-4.5 1-1.5 ~0.8 Clerance (ml/kg/min) 30-60 6-8 ~1.50 Protein binding 98% 98% 85% Distribution half time 2-4 mins ~20 mins 8-10 mins Onset time ~30 secs 30-60 secs iv 25-30 mins p.o / im ~15 secs Peak effect time ~90 secs 3-5 mins ~30-40 secs Duration of action 8-10 mins 15-80 mins 5-15 mins Hepatic failure (cirrhosis) No effect May increase duration Any change is unlikely May increase duration Renal failure No effect Not altered Any change is unlikely

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